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1.
ACS Omega ; 6(44): 29675-29684, 2021 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-34778639

RESUMO

Owing to many problems of the detriment by large amount of organic reagents, high cost and difficulty of industrialization, development of high-efficiency economical technologies for uranium extraction is an irresistible trend to support steady supply of nuclear energy. Herein, a novel fibrous adsorbent, named as AO-HPE fibers, was prepared by introduction of amidoxime groups using the green vapor-phase grafting polymerization (VPGP) technology of monomer acrylonitrile (AN). Gaseous AN was grafted onto the ultra high molecular weight polyethylene (UHMWPE) fibers at 80 °C in the enclosed evaporation and condensation reflux system. The innovative technology not only endowed synthetic process high monomer utilization ratio but also excellent environmental friendliness. The AO-HPE fibers exhibited an appreciable calculated maximum adsorption capacity (Q m) of 1144.94 mg·g-1 in uranium solution and an adsorption capacity of 14.11 mg·g-1 in simulated seawater. Meanwhile, the higher uranium selectivity than main competing ion vanadium (adsorption mass ratio was almost 5) was achieved. The adsorption process accorded closely with chemisorption mechanism. This work provided a novel idea for the synthetic method of adsorbents for uranium extraction, and inspired the sustainable technologies for grafting polymerization of monomer AN.

2.
Mol Pain ; 17: 17448069211050246, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34806494

RESUMO

Migraine is the second most prevalent disorder in the world; yet, its underlying mechanisms are still poorly understood. Cumulative studies have revealed pivotal roles of cerebral cortex in the initiation, propagation, and termination of migraine attacks as well as the interictal phase. Investigation of basic mechanisms of the cortex in migraine not only brings insight into the underlying pathophysiology but also provides the basis for designing novel treatments. We aim to summarize the current research literatures and give a brief overview of the cortex and its role in migraine, including the basic structure and function; structural, functional, and biochemical neuroimaging; migraine-related genes; and theories related to cortex in migraine pathophysiology. We propose that long-term plasticity of synaptic transmission in the cortex encodes migraine.

3.
Mol Pain ; 17: 17448069211047863, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34761717

RESUMO

Lack of uricase leads to the high incidence of gout in humans and poultry, which is different from rodents. Therefore, chicken is considered to be one of the ideal animal models for the study of gout. Gout-related pain caused by the accumulation of urate in joints is one type of inflammatory pain, which causes damage to joint function. Our previous studies have demonstrated the crucial role of calcium-stimulated adenylyl cyclase subtype 1 (AC1) in inflammatory pain in rodents; however, there is no study in poultry. In the present study, we injected mono-sodium urate (MSU) into the left ankle joint of the chicken to establish a gouty arthritis model, and tested the effect of AC1 inhibitor NB001 on gouty arthritis in chickens. We found that MSU successfully induced spontaneous pain behaviors including sitting, standing on one leg, and limping after 1-3 h of injection into the left ankle of chickens. In addition, edema and mechanical pain hypersensitivity also occurred in the left ankle of chickens with gouty arthritis. After peroral administration of NB001 on chickens with gouty arthritis, both the spontaneous pain behaviors and the mechanical pain hypersensitivity were effectively relieved. The MSU-induced edema in the left ankle of chickens was not affected by NB001, suggesting a central effect of NB001. Our results provide a strong evidence that AC1 is involved in the regulation of inflammatory pain in poultry. A selective AC1 inhibitor NB001 produces an analgesic effect (not anti-inflammatory effect) on gouty pain and may be used for future treatment of gouty pain in both humans and poultry.

4.
Acta Pharm Sin B ; 11(10): 3244-3261, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34729313

RESUMO

Major challenges for cancer treatment are how to effectively eliminate primary tumor and sufficiently induce immunogenic cell death (ICD) to provoke a robust immune response for metastasis control. Here, a self-assembled cascade bioreactor was developed to improve cancer treatment with enhanced tumor penetration and synergistic therapy of starvation, chemodynamic (CDT) and photothermal therapy. Ultrasmall FeS-GOx nanodots were synthesized with glucose oxidase (GOx) as template and induced by paclitaxel (PTX) to form self-assembling FeS-GOx@PTX (FGP) via hydrophobic interaction. After accumulated at tumor sites, FGP disassembles to smaller FeS-GOx for enhanced deep tumor penetration. GOx maintains high enzymatic activity to catalyze glucose with assistant of oxygen to generate hydrogen peroxide (H2O2) as starvation therapy. Fenton reaction involving the regenerated H2O2 in turn produced more hydroxyl radicals for enhanced CDT. Following near-infrared laser at 808 nm, FGPs displayed pronounced tumor inhibition in vitro and in vivo by the combination therapy. The consequent increased exposure to calreticulin amplified ICD and promoted dendritic cells maturation. In combination with anti-CTLA4 checkpoint blockade, FGP can absolutely eliminate primary tumor and avidly inhibit distant tumors due to the enhanced intratumoral infiltration of cytotoxic T lymphocytes. Our work presents a promising strategy for primary tumor and metastasis inhibition.

5.
J Chem Phys ; 155(17): 174301, 2021 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-34742224

RESUMO

The shuttling effect is a crucial obstacle to the practical deployment of lithium sulfur batteries (LSBs). This can be ascribed to the generation of lithium polysulfide (LiPS) redox intermediates that are soluble in the electrolyte. The detailed mechanism of the shuttling, including the chemical structures responsible for the loss of effective mass and the dynamics/kinetics of the redox reactions, are not clear so far. To obtain this microscopic information, characterization techniques with high spatial and temporal resolutions are required. Here, we propose that resonance Raman spectroscopy combined with ultrafast broadband pulses is a powerful tool to reveal the mechanism of the shuttling effect. By combining the chemical bond level spatial resolution of resonance Raman and the femtosecond scale temporal resolution of the ultrafast pulses, this novel technique holds the potential of capturing the spectroscopic fingerprints of the LiPS intermediates during the working stages of LSBs. Using ab initio simulations, we show that, in addition to the excitation energy selective enhancement, resonance Raman signals of different LiPS intermediates are also characteristic and distinguishable. These results will facilitate the real-time in situ monitoring of LiPS species and reveal the underlying mechanism of the shuttling effect.

6.
Front Nutr ; 8: 714291, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34746202

RESUMO

Background: Evidence of an association between dairy product and main related dairy nutrient intake, and the asthenozoospermia risk have been limited and controversial. Methods: A hospital-based case-control study including 549 men with asthenozoospermia and 581 normozoospermic controls was carried out in the infertility clinics of Shengjing Hospital of China Medical University between June, 2020 and December, 2020. Dietary intake was assessed with a validated food frequency questionnaire. According to the World Health Organization guidelines, semen parameters were collected through masturbation and were measured with WLJY9000 instrument and flow cytometry. The daily intake of dairy products and related nutrients was categorized into three groups according to control distribution, and the lowest tertile was used as the reference category. An unconditional multiple logistic regression was used to estimate the odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) for asthenozoospermia risk. Results: After adjustment for potential confounders, we found no statistically significant associations between the intake of total dairy products and asthenozoospermia risk (ORT3vs.T1 = 1.19, 95%CI = 0.85-1.67). Additionally, we generated null findings regarding the main related nutrients from dairy, including protein (ORT3vs.T1 = 1.19, 95%CI = 0.85-1.68), fat (ORT3vs.T1 = 1.28, 95%CI = 0.91-1.80), calcium (ORT3vs.T1 = 1.20, 95%CI = 0.85-1.68), saturated fatty acids (ORT3vs.T1 = 1.30, 95%CI = 0.92-1.83), and phosphorous (ORT3vs.T1 = 1.18, 95%CI = 0.84-1.67), and the asthenozoospermia risk. Of note, after stratification by body mass index (BMI), and the saturated fatty acids consumption from dairy was significantly associated with a higher asthenozoospermia risk (ORT3vs.T1 = 1.76, 95%CI = 1.01-3.09) among participants with a BMI below 25 kg/m2. Conclusion: This study provided limited evidence of an association between the intake of total dairy products and the main related dairy nutrients including protein, fat, calcium, saturated fatty acids, and phosphorus, and the asthenozoospermia risk. Further studies are warranted to confirm our findings in the future.

7.
Front Immunol ; 12: 745109, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34603332

RESUMO

T-cell therapy, usually with ex-vivo expansion, is very promising to treat cancer. Differentiation status of infused T cells is a crucial parameter for their persistence and antitumor immunity. Key phenotypic molecules are effective and efficient to analyze differentiation status. Differentiation status is crucial for T cell exhaustion, in-vivo lifespan, antitumor immunity, and even antitumor pharmacological interventions. Strategies including cytokines, Akt, Wnt and Notch signaling, epigenetics, and metabolites have been developed to produce less differentiated T cells. Clinical trials have shown better clinical outcomes from infusion of T cells with less differentiated phenotypes. CD27+, CCR7+ and CD62L+ have been the most clinically relevant phenotypic molecules, while Tscm and Tcm the most clinically relevant subtypes. Currently, CD27+, CD62L+ and CCR7+ are recommended in the differentiation phenotype to evaluate strategies of enhancing stemness. Future studies may discover highly clinically relevant differentiation phenotypes for specific T-cell production methods or specific subtypes of cancer patients, with the advantages of precision medicine.

8.
Artigo em Inglês | MEDLINE | ID: mdl-34613377

RESUMO

OBJECTIVES: In this study, we developed an IS26-based CRISPR/Cas9 system as a proof-of-concept study to explore the potential of a re-engineered bacterial translocatable unit (TU) for curing and immunizing against the replication genes and antimicrobial resistance genes. METHODS: A series of pIS26-CRISPR/Cas9 suicide plasmids were constructed, and specific guide RNAs were designed to target the replication gene of IncX4, IncI2 and IncHI2 plasmids, and the antibiotic resistance genes mcr-1, blaKPC-2 and blaNDM-5. Through conjugation and induction, the transposition efficiency and plasmid-curing efficiency in each recipient were tested. In addition, we examined the efficiency of the IS26-CRISPR/Cas9 system of cell immunity against the acquisition of the exogenous resistant plasmids by introducing this system into antimicrobial-susceptible hosts. RESULTS: This study aimed to eliminate the replication genes and antimicrobial resistance genes using pIS26-CRISPR/Cas9. Three plasmids with different replicon types, including IncX4, IncI2 and IncHI2 in three isolates, two pUC19-derived plasmids, pUC19-mcr-1 and pUC19-IS26mcr-1, in two lab strains, and two plasmids bearing blaKPC-2 and blaNDM-5 in two isolates were all successfully eliminated. Moreover, the IS26-based CRISPR/Cas9 system that remained in the plasmid-cured strains could efficiently serve as an immune system against the acquisition of the exogenous resistant plasmids. CONCLUSIONS: The IS26-based CRISPR/Cas9 system can be used to efficiently sensitize clinical Escherichia coli isolates to antibiotics in vitro. The single-guide RNAs targeted resistance genes or replication genes of specific incompatible plasmids that harboured resistance genes, providing a novel means to naturally select bacteria that cannot uptake and disseminate such genes.

9.
Front Cell Neurosci ; 15: 720271, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34658791

RESUMO

Background: Spinal cord injury (SCI) is a highly lethal and debilitating disease with a variety of etiologies. To date, there is no effective therapeutic modality for a complete cure. The pathological mechanisms of spinal cord injury at the molecular gene and protein expression levels remain unclear. Methods: This study used single-cell transcriptomic analysis and protein microarray analysis to analyzes changes in the gene expression profiles of cells and secretion of inflammatory factors respectively, around the lesion site in a rat SCI model. Results: Single-cell transcriptomic analysis found that three types of glial cells (microglia, astrocyte, and oligodendrocyte) becomes activated after acute injury, with GO exhibiting a variety of inflammatory-related terms after injury, such as metabolic processes, immune regulation, and antigen presentation. Protein microarray results showed that the levels of four inflammatory cytokines favoring SCI repair decreased while the levels of nine inflammatory cytokines hindering SCI repair increased after injury. Conclusion: These findings thus reveal the changes in cellular state from homeostatic to reactive cell type after SCI, which contribute to understand the pathology process of SCI, and the potential relationship between glial cells and inflammatory factors after SCI, and provides new theoretical foundation for further elucidating the molecular mechanisms of secondary SCI.

10.
J Physiol Biochem ; 2021 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-34657993

RESUMO

As a highly evolutionarily conserved process, autophagy can be found in all types of eukaryotic cells. Such a constitutive process maintains cellular homeostasis in a wide variety of cell types through the encapsulation of damaged proteins or organelles into double-membrane vesicles. Autophagy not only simply eliminates materials but also serves as a dynamic recycling system that produces new building blocks and energy for cellular renovation and homeostasis. Previous studies have primarily recognized the role of autophagy in the degradation of dysfunctional proteins and unwanted organelles. However, there are findings of autophagy in physiological and pathological processes. In hepatocytes, autophagy is not only essential for homeostatic functions but also implicated in some diseases, such as viral hepatitis, alcoholic hepatitis, and hepatic failure. In the present review, we summarized the molecular mechanisms of autophagy and its role in several liver diseases and put forward several new strategies for the treatment of liver disease.

11.
Materials (Basel) ; 14(19)2021 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-34640006

RESUMO

Land desertification, a severe global ecological and environmental problem, brings challenges to the sustainable utilization of land resources in the world. The purpose of this research is to use hydrophobic theory to prepare impervious and breathable sand, and to solve the problems of sandy soil that seeps easily and makes it difficult for vegetation to survive in desertified areas. The influences of coating material content, first-level and second-level rough structure on the impermeability and air permeability of impervious and breathable sand were studied. The research showed that, with the increase in coating material content, the impervious performance of the sample increased firstly and then decreased, and the air permeability rose continuously. The hydrostatic pressure resistance of the sample can reach an extreme value of 53 mm. The first-level rough structure of micron structure can greatly improve the hydrophobic performance, thus improving the impervious performance. The addition of micron calcium carbonate would improve the hydrostatic pressure resistance height of the sample to 190 mm. The sample would reach a superhydrophobic state in the condition of a first-level rough structure of a nano structure built by nano silica, and the contact angle was up to 152.0°, so that the hydrostatic pressure resistance height can rise to 205 mm. The best performance would be achieved under the condition of relatively less raw material with a second-level rough structure of micro-nano. At this point, the contact angle of the sample reached 152.8° and the hydrostatic pressure resistance height was up to 205 mm. At the same time, the air permeability index of the above four kinds of impervious and breathable sand met all planting requirements. The sample prepared can satisfy the demands of different degrees of impermeability and air permeability, and can be widely used in desertification control.

13.
BMC Med Imaging ; 21(1): 132, 2021 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-34503482

RESUMO

BACKGROUND: Simultaneous multislice diffusion-weighted imaging (SMS-DWI) has been used to reduce image acquisition time. The purpose of this study was to investigate the feasibility of diffusion kurtosis imaging (DKI) based on the SMS technique in the liver and the influence of this method compared with that of conventional DWI sequences on image quality and DKI-derived quantitative parameters. METHODS: Forty volunteers underwent SMS-DWI sequences with acceleration factors of 2 and 3 (SMS2-DWI, SMS3-DWI) and conventional DWI (C-DWI) of the liver with three b-values (50, 800, 2000 s/mm2) in a 3T system. Qualitative image quality parameters and quantitative measurements of the signal-to-noise ratio (SNR), mean kurtosis (MK), mean apparent diffusivity (MD) and apparent diffusion coefficient (ADC) for the liver were compared between the three sequences. RESULTS: The scan times of C-DWI, SMS2-DWI, and SMS3-DWI were 4 min 11 s, 2 min 2 s, and 1 min 34 s, respectively. For all image quality parameters, there were no significant differences observed between C-DWI and SMS2-DWI (all p > 0.05) in the images with b-values of 800 and 2000 s/mm2. C-DWI and SMS2-DWI exhibited better scores than SMS3-DWI (all p < 0.01) in the images with b-values of 2000 s/mm2. In the images with b-values of 800 s/mm2, C-DWI and SMS2-DWI exhibited better scores than SMS3-DWI for artefacts and overall image quality (all p < 0.01), and C-DWI exhibited better scores than SMS3-DWI for the visibility of intrahepatic vessels (p < 0.001). There were no significant differences in the sharpness of the right lobe edge (p = 0.144), conspicuity of the left lobe (p = 0.370) or visibility of intrahepatic vessels (p = 0.109) between SMS2-DWI and SMS3-DWI. There were no significant differences in the sharpness of the right lobe edge (p = 0.066) or conspicuity of the left lobe (p = 0.131) between C-DWI and SMS3-DWI. For the b-value of 800 s/mm2, there were no statistically significant differences between SMS2-DWI and C-DWI (p = 1.000) or between SMS2-DWI and SMS3-DWI (p = 0.059), whereas SMS3-DWI had a significantly lower SNR than C-DWI (p = 0.024). For the DKI-derived parameters (MK and MD) and ADC values, there were no significant differences between the three sequences (MK, p = 0.606; MD, p = 0.831; ADC, p = 0.264). CONCLUSIONS: SMS-DWI with an acceleration factor of 2 is feasible for the liver, resulting in considerable reductions in scan time while maintaining similar image quality, comparable DKI parameters and ADC values compared with those of C-DWI.

14.
Cancers (Basel) ; 13(17)2021 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-34503126

RESUMO

Tumor heterogeneity results in more than 50% of hypermutated cancers failing to respond to standard immunotherapy. There are numerous challenges in terms of drug resistance, therapeutic strategies, and biomarkers in immunotherapy. In this study, we analyzed primary tumor samples from 533 cancer patients with six different cancer types using deep targeted sequencing and gene expression data from 78 colorectal cancer patients, whereby driver mutations, mutational signatures, tumor-associated neoantigens, and molecular cancer evolution were investigated. Driver mutations, including RET, CBL, and DDR2 gene mutations, were identified in the hypermutated cancers. Most hypermutated endometrial and pancreatic cancer patients carry genetic mutations in EGFR, FBXW7, and PIK3CA that are linked to immunotherapy resistance, while hypermutated head and neck cancer patients carry genetic mutations associated with better treatment responses, such as ATM and BRRCA2 mutations. APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) and DNA repair defects are mutational drivers that are signatures for hypermutated cancer. Cancer driver mutations and other mutational signatures are associated with sensitivity or resistance to immunotherapy, representing potential genetic markers in hypermutated cancers. Using computational prediction, we identified NF1 p.T700I and NOTCH1 p.V2153M as tumor-associated neoantigens, representing potential therapeutic targets for immunotherapy. Sequential mutations were used to predict hypermutated cancers based on genomic evolution. Using a logistic model, we achieved an area under the curve (AUC) = 0.93, accuracy = 0.93, and sensitivity = 0.81 in the testing set. The sequential patterns were distinct among the six cancer types, and the sequential mutation order of MSH2 and the coexisting BRAF genetic mutations influenced the hypermutated phenotype. The TP53~MLH1 and NOTCH1~TET2 sequential mutations impacted colorectal cancer survival (p-value = 0.027 and 0.0001, respectively) by reducing the expression of PTPRCAP (p-value = 1.06 × 10-6) and NOS2 (p-value = 7.57 × 10-7) in immunity. Sequential mutations are significant for hypermutated cancers, which are characterized by mutational heterogeneity. In addition to driver mutations and mutational signatures, sequential mutations in cancer evolution can impact hypermutated cancers. They characterize potential responses or predictive markers for hypermutated cancers. These data can also be used to develop hypermutation-associated drug targets and elucidate the evolutionary biology of cancer survival. In this study, we conducted a comprehensive analysis of mutational patterns, including sequential mutations, and identified useful markers and therapeutic targets in hypermutated cancer patients.

15.
J Am Chem Soc ; 143(37): 15378-15390, 2021 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-34478271

RESUMO

The artificial engineering of an enzyme's structural conformation to enhance its activity is highly desired and challenging. Anisotropic reticular chemistry, best illustrated in the case of multivariate metal-organic frameworks (MTV-MOFs), provides a platform to modify a MOF's pore and inner-surface with functionality variations on frameworks to optimize the interior environment and to enhance the specifically targeted property. In this study, we altered the functionality and ratio of linkers in zeolitic imidazolate frameworks (ZIFs), a subclass of MOFs, with the MTV approach to demonstrate a strategy that allows us to optimize the activity of the encapsulated enzyme by continuously tuning the framework-enzyme interaction through the hydrophilicity change in the pores' microenvironment. To systematically study this interaction, we developed the component-adjustment-ternary plot (CAT) method to approach the optimal activity of the encapsulated enzyme BCL and revealed a nonlinear correlation, first incremental and then decremental, between the BCL activity and the hydrophilic linker' ratios in MTV-ZIF-8. These findings indicated there is a spatial arrangement of functional groups along the three-dimensional space across the ZIF-8 crystal with a unique sequence that could change the enzyme structure between closed-lid and open-lid conformations. These conformation changes were confirmed by FTIR spectra and fluorescence studies. The optimized BCL@ZIF-8 is not only thermally and chemically more stable than free BCL in solution, but also doubles the catalytic reactivity in the kinetic resolution reaction with 99% ee of the products.

16.
Cardiovasc Res ; 2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-34352088

RESUMO

AIMS: Recent studies have shown that the choline-derived metabolite trimethylamine N-oxide (TMAO) is a biomarker that promotes cardiovascular disease through the induction of inflammation and stress. Inflammatory responses and stress are involved in the progression of calcified aortic valve disease (CAVD). Here, we examined whether TMAO induces the osteogenic differentiation of aortic valve interstitial cells (AVICs) through endoplasmic reticulum (ER) and mitochondrial stress pathways in vitro and in vivo. METHODS AND RESULTS: Plasma TMAO levels were higher in patients with CAVD (n = 69) than in humans without CAVD (n = 263), as examined by liquid chromatography-tandem mass spectrometry. Western blot and staining probes showed that TMAO- induced an osteogenic response in human AVICs. Moreover, TMAO promoted ER stress, mitochondrial stress and NF-κB activation in vitro. Notably, the TMAO- mediated effects were reversed by the use of ER stress, mitochondrial stress and NF-κB activation inhibitors and siRNA. Mice treated with supplemental choline in a high fat diet had markedly increased TMAO levels and aortic valve thicknesses, which were reduced by 3,3-dimethyl-1-butanol (DMB, an inhibitor of trimethylamine formation) treatment. CONCLUSIONS: Choline-derived TMAO promotes osteogenic differentiation through ER and mitochondrial stress pathways in vitro and aortic valve lesions in vivo. TRANSLATIONAL PERSPECTIVE: Trimethylamine-N-oxide (TMAO), a gut microbiota-generated metabolite, is associated with cardiovascular diseases. Here, we show that patients with calcified aortic valve disease (CAVD) have elevated circulating TMAO levels. TMAO induces osteogenic responses in human aortic valve interstitial cells via endoplasmic reticulum-mitochondrial stress in vitro and aggravates aortic valve lesions in mice. This may provide clues to the pathogenesis of CAVD and attractive potential targets for the prevention, diagnosis and treatment of this disease.

17.
Int J Gen Med ; 14: 4197-4207, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34385840

RESUMO

Objective: To evaluate the long-term outcomes after drug-coated balloon (DCB) angioplasty dissection in patients with complex femoropopliteal artery disease. Methods: Two hundred patients with femoropopliteal peripheral artery disease were enrolled in the AcoArt I trial and randomly assigned to either the DCB or percutaneous transluminal angioplasty (PTA) group. A total of 86 patients with post-balloon angioplasty dissection were reanalyzed. The primary endpoint was clinically driven target lesion revascularization (CD-TLR) over five years. Kaplan-Meier curve estimates were used to evaluate the association between the treatment and CD-TLR. Interaction and stratified analyses were also performed. Results: Over five years, patients treated with DCB angioplasty demonstrated an acceptable effect with a numerically higher but not statistically significant rate of freedom from CD-TLR compared with those treated by PTA (Kaplan-Meier estimate of 77.6% vs 64.4%; log-rank P = 0.08). Among the patients who underwent TLR, the mean time from intervention to TLR in the DCB group was significantly prolonged compared to the PTA group (P < 0.001). The stratified analysis showed that the Rutherford classification played an interactive role in the association between the DCB angioplasty and low CD-TLR rate at five years. No significant difference in the all-cause mortality was found in the patients with post-balloon angioplasty dissection between the two treatment groups. Conclusion: The five-year follow-up outcomes of the post-balloon angioplasty dissection in the AcoArt I trial demonstrated that DCB angioplasty is more trustworthy than PTA, with a higher rate of freedom than CD-TLR and sustained improvement in clinical symptoms. However, the all-cause mortality rate in patients with femoropopliteal lesions is similar after both DCB angioplasty and PTA. Clinical Trial Registration: http://www.clinicaltrials.gov. Unique Identifier: NCT01850056.

18.
Sci Total Environ ; 799: 149360, 2021 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-34365265

RESUMO

Tetracycline antibiotics (TCs) are massively produced and consumed in various industries resulting in large quantities of residuals in the environment. In this study, to achieve safe and efficient removal of residual TCs, a Pichia pastoris (P. pastoris) was gained to stably express glycosylated TCs degrading enzyme Tet(X) followed codon and expression parameter optimization of tet(X4). As expected, glycosylated Tet(X) still maintains efficient capacity of degrading TCs. The expressed Tet(X) maintained efficient TCs degrading ability over a pH range of 6.5 - 9.5 and temperature range of 17 - 47 °C. We tested this recombinant protein for its ability to degrade tetracycline in pond water and sewage models of tetracycline removal at starting levels of 10 mg/L substrate. 80.5 ± 3.8% and 26.2 ± 2.6% of tetracycline was degraded within 15 min in the presence of 0.2 µM Tet(X) and 50 µM NADPH, respectively. More importantly, the direct use of a Tet(X) degrading enzymes reduces the risk of gene transmission during degradation. Thus, the Tet(X) degrading enzyme expressed by P. pastoris is an effective and safe method for treating intractable TCs residues.


Assuntos
Pichia , Tetraciclinas , Antibacterianos , Pichia/genética , Saccharomycetales , Água
19.
Antimicrob Agents Chemother ; 65(10): e0105421, 2021 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-34339270

RESUMO

The global spread of antimicrobial-resistant bacteria has been one of the most severe threats to public health. The emergence of the mcr-1 gene has posed a considerable threat to antimicrobial medication since it deactivates one last-resort antibiotic, colistin. There have been reports regarding the mobilization of the mcr-1 gene facilitated by ISApl1-formed transposon Tn6330 and mediated rapid dispersion among Enterobacteriaceae species. Here, we developed a CRISPR/Cas9 system flanked by ISApl1 in a suicide plasmid capable of exerting sequence-specific curing against the mcr-1-bearing plasmid and killing the strain with chromosome-borne mcr-1. The constructed ISApl1-carried CRISPR/Cas9 system either restored sensitivity to colistin in strains with plasmid-borne mcr-1 or directly eradicated the bacteria harboring chromosome-borne mcr-1 by introducing an exogenous CRISPR/Cas9 targeting the mcr-1 gene. This method is highly efficient in removing the mcr-1 gene from Escherichia coli, thereby resensitizing these strains to colistin. The further results demonstrated that it conferred the recipient bacteria with immunity against the acquisition of the exogenous mcr-1 containing the plasmid. The data from the current study highlighted the potential of the transposon-associated CRISPR/Cas9 system to serve as a therapeutic approach to control the dissemination of mcr-1 resistance among clinical pathogens.


Assuntos
Proteínas de Escherichia coli , Escherichia coli , Antibacterianos/farmacologia , Sistemas CRISPR-Cas/genética , Cromossomos , Colistina/farmacologia , Farmacorresistência Bacteriana/genética , Escherichia coli/genética , Proteínas de Escherichia coli/genética , Humanos , Plasmídeos/genética
20.
Theranostics ; 11(17): 8587-8604, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34373760

RESUMO

Background: Sonodynamic therapy (SDT) is a promising strategy to inhibit tumor growth and activate antitumor immune responses for immunotherapy. However, the hypoxic and immunosuppressive tumor microenvironment limits its therapeutic efficacy and suppresses immune response. Methods: In this study, mitochondria-targeted and ultrasound-responsive nanoparticles were developed to co-deliver oxygen (O2) and nitric oxide (NO) to enhance SDT and immune response. This system (PIH-NO) was constructed with a human serum albumin-based NO donor (HSA-NO) to encapsulate perfluorodecalin (FDC) and the sonosensitizer (IR780). In vitro, the burst release of O2 and NO with US treatment to generate reactive oxygen species (ROS), the mitochondria targeting properties and mitochondrial dysfunction were evaluated in tumor cells. Moreover, in vivo, tumor accumulation, therapeutic efficacy, the immunosuppressive tumor microenvironment, immunogenic cell death, and immune activation after PIH-NO treatment were also studied in 4T1 tumor bearing mice. Results: PIH-NO could accumulate in the mitochondria and relive hypoxia. After US irradiation, O2 and NO displayed burst release to enhance SDT, generated strongly oxidizing peroxynitrite anions, and led to mitochondrial dysfunction. The release of NO increased blood perfusion and enhanced the accumulation of the formed nanoparticles. Owing to O2 and NO release with US, PIH-NO enhanced SDT to inhibit tumor growth and amplify immunogenic cell death in vitro and in vivo. Additionally, PIH-NO promoted the maturation of dendritic cells and increased the number of infiltrating immune cells. More importantly, PIH-NO polarized M2 macrophages into M1 phenotype and depleted myeloid-derived suppressor cells to reverse immunosuppression and enhance immune response. Conclusion: Our findings provide a simple strategy to co-deliver O2 and NO to enhance SDT and reverse immunosuppression, leading to an increase in the immune response for cancer immunotherapy.

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